Human tumor necrosis factor-alpha (TNFα) is a homotrimer consisting of three 17 kDa protein subunits (Eck M. J. et al., JBC, 267: 2119-2122, 1992; Smith R. A. et al., JBC, 262: 6951-6954, 1987). TNFα is an inflammatory cytokine secreted from macrophages and monocytes, and functions as a signal transmitter in several cellular reactions such as necrosis and apoptosis (Beyaert R. et al., FEBS Lett., 340: 9-16, 1994). TNFα causes a pro-inflammatory action leading to tissue destruction, such as breakdown of the cartilage and bone (Saklatvala, Nature, 322: 547-549, 1986), induction of procoagulation activity in vascular endothelial cells (Pober J S et al., J. Immunol., 136; 1680-1687, 1986), and increase in the adherence of neutrophils and lymphocytes (Pober et al., J. Immunol. 138: 3319-3324, 1987).
The pathology of a variety of disorders is attributed to excessive amounts of TNFα, either locally or systemically. For example, there is strong evidence that abnormally high production and release from cells of TNFα contributes to disease initiation and progression in rheumatoid arthritis, systemic inflammatory syndromes, diabetes, and multiple sclerosis. In every one of these conditions, the initiating and sustaining pathophysiologic action is directly a result of an immediate local release and synthesis of massive amounts of TNFα from several types of cells at or adjacent to the site of tissue damage. The locally released TNFα is followed by additional synthesis and release of TNFα by invading macrophages drawn to the site of tissue damage by a cascade of chemotactic cytokines released locally from cells in response to the greatly elevated TNFα concentrations.
There is a constant demand in the art for new antibodies that bind and neutralize TNFα.